AAAAI 2023 Data Identify Dysregulated Pathways in Hereditary Angioedema Prodromes and Acute Attacks

During the American Academy of Allergy, Asthma & Immunology (AAAAI) 2023 Annual Meeting, new research was presented on the potential advantages of treating early symptoms or prodromes of hereditary angioedema (HAE) to prevent acute attacks.

Results emphasized the significance of transcriptomic analysis to comprehend the molecular mechanisms involved in the treatment and underlying causes of the rare disease.

Hereditary angioedema is a condition characterized by swelling of the face, lips, and eyes, which can be potentially life-threatening if it affects the airways and alveoli. HAE is associated with a protein called C1 esterase inhibitor, which can lead to a deficiency or deformation of the protein, making patients susceptible to the disease.

The study was led by AAAAI presenter Debajyoti Ghosh, PhD, Research Instructor, Internal Medicine, University of Cincinnati. The motive was to investigate whether there is an overlap between blood transcriptomic changes in patients with HAE during a prodrome, occurring in 85% of patients prior to an attack, and changes observed pre- and post-treatment of an acute attack, following treatment of the prodrome with recombinant human C1-INH (Ruconest).

Treating HAE Attack with Recombinant Human C1-INH

The multi-center, unblinded, case-crossover investigation randomly assigned patients with hereditary angioedema to prodrome or attack-treatment groups. After 2 prodromes or 2 attacks, patients were crossed-over to attack or prodrome treatment groups. All patients were treated during the prodrome or acute attack with recombinant human C1-INH.

Blood samples for analysis by RNAseq were obtained during baseline, prodrome before and after prodrome treatment, attack onset before and after attack treatment. Differentially regulated genes and pathways were elucidated by Ingenuity Pathway Analysis (IPA, Qiagen).

The study found that HAE prodromes were associated with upregulation of multiple inflammatory extracellular matrix genes, neuropeptide, and inflammasome member genes, such as SPARCL1, AGRP, and NLRP9. Recombinant human C1-INH treatment resulted in the reversal of the disease signature in HAE-associated dysregulated pathways.

Moreover, approximately 42% of prodrome-associated DEGs were also associated with HAE attacks, indicating that multiple enriched gene networks with common hub genes and upstream regulators, such as TNF, NONO, and CXCL8, are shared between the prodromal and acute attack stages of HAE.

These results have significant implications for the clinical management of HAE and suggest that treating prodromes may be a viable strategy for preventing acute attacks in this population. The findings also highlighted the importance of transcriptomic analysis in understanding the molecular mechanisms underlying HAE and its treatment.

Living with hereditary angioedema can potentially become fatal, and the indications of these findings illuminated treatment of prodromes as a possible viable strategy for preventing acute attacks.

References:

1. Ghosh D, Singh U, Anderson J, Bernstein J. Biologic Pathways Involved In Hereditary Angioedema And Response To Ruconest® Treatment during prodrome and attack. Journal of Allergy and Clinical Immunology. 2023;151(2):AB340.